The goal of this project is to determine the effects of controlling weight gain by energy restriction, physical activity, or their combination on the carcinogenic process in an experimental model for breast cancer, and to assess how dietary carbohydrate availability modulates responses as outlined in the followings aims. Aim 1. Determine the effects of energy restriction or physical activity alone or in combination on the carcinogenic response in the mammary gland and on candidate markers for cancer risk. This model is built on the human model in Project 4 but extends observation to related pathways/processes in the target tissue. This work will be conducted using a well characterized rodent model for breast cancer and a rodent exercise device newly developed by our laboratory in which a variable speed, motorized activity wheel is linked, under computer control, to a food pellet dispenser so that physical activity behavior is maintained by positive food reward. Effects of these interventions on the carcinogenic process, on factors involved in glucose homeostasis, and on indicators of inflammation and oxidative damage will be measured. As in Project 1 we will seek to determine how cell proliferation, apoptosis, and angiogenesis are modulated. Aim 2. Assess the effect of carbohydrate availability on the carcinogenic response and systemic biomarkers when weight control is mediated by energy restriction and observe of pathways and processes in the target tissue. There is considerable speculation but few experimental data to inform the debate about the consequences on disease risk of popular weight loss/maintenance diets that differ in carbohydrate availability. Preliminary studies have established the feasibility of feeding the same diets used in the human feeding study proposed in Project 3 in our pre-clinical animal model. Aim 3. Investigate candidate mechanisms and markers using genomic and proteomic technologies in order to elucidate target pathways for prevention. Human beings vary in the amount (dose) of energy restriction or physical activity in which they engage to control weight. Available pre-clinical data indicate that different mechanisms may underlie the prevention of cancer by these interventions depending on intervention dose. cDNA microarray analyses will be used to detect differences in the pathways induced in response to energy restriction or physical activity dose and proteomic technologies performed in Core C will be employed to discover serum biomarker profiles that reflect the modulation of the carcinogenic response by these interventions.